Targeted disruption of the JAK2/STAT3 pathway in combination with systemic administration of paclitaxel inhibits the priming of ovarian cancer stem cells leading to a reduced tumor burden

Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo,we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7 days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients.

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ~2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10-9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10-12, and -0.16 SD per G allele, P = 1.2×10-15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10-9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10-6 and rs2707466: OR = 1.22, P = 7.2×10-6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16-/- mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10-13<P<5.9×10-4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture. © 2012 Zheng et al.

Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates

Gene-targeted disruption of Grg5, a mouse homologue of Drosophila groucho (gro), results in postnatal growth retardation in mice. The growth defect, most striking in approximately half of the Grg5 null mice, occurs during the first 4-5 weeks of age, but most mice recover retarded growth later. We used the nonlinear mixed-effects model to fit the growth data of wild-type, heterozygous, and Grg5 null mice. On the basis of preliminary evidence suggesting an interaction between Grg5 and the transcription factor Cbfa1/Runx2, critical for skeletal development, we further investigated the skeleton in the mice. A long bone growth plate defect was identified, which included shorter zones of proliferative and hypertrophic chondrocytes and decreased trabecular bone formation. This decreased trabecular bone formation is likely caused by a reduced recruitment of osteoblasts into the growth plate region of Grg5 null mice. Like the growth defect, the growth plate and trabecular bone abnormality improved as the mice grew older. The growth plate defect was associated with reduced Indian hedgehog expression and signaling. We suggest that Grg5, a transcriptional coregulator, modulates the activities of transcription factors, such as Cbfa1/Runx2 in vivo to affect Ihh expression and the function of long bone growth plates.

Dopamine responsiveness is regulated by targeted sorting of D2 receptors

Abstract Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.

The user-led disruption : self-(re)broadcasting at Justin.tv and elsewhere

The rise of videosharing and self-(re)broadcasting Web services is posing new threats to a television industry already struggling with the impact of filesharing networks. This paper outlines these threats, focussing especially on the DIY re-broadcasting of live sports using Websites such as Justin.tv and a range of streaming media networks built on peer-to-peer filesharing technology.

Images of desire : cognitive models of craving

Cognitive modelling of phenomena in clinical practice allows the operationalisation of otherwise diffuse descriptive terms such as craving or flashbacks. This supports the empirical investigation of the clinical phenomena and the development of targeted treatment interventions. This paper focuses on the cognitive processes underpinning craving, which is recognised as a motivating experience in substance dependence. We use a high-level cognitive architecture, Interacting Cognitive Subsystems (ICS), to compare two theories of craving: Tiffany's theory, centred on the control of automated action schemata, and our own Elaborated Intrusion theory of craving. Data from a questionnaire study of the subjective aspects of everyday desires experienced by a large non-clinical population are presented. Both the data and the high-level modelling support the central claim of the Elaborated Intrusion theory that imagery is a key element of craving, providing the subjective experience and mediating much of the associated disruption of concurrent cognition.

An adolescent injury intervention : selecting targeted behaviours with implications for program design and evaluation

Objectives: This paper sought to identify the behaviour change targets for an injury prevention program; Skills for Preventing Injury in Youth, SPIY. The aim was to explore how such behaviours could subsequently be implemented and evaluated in the program. Methods and Design: The quantitative procedure involved a survey with 267 Year 8 and 9 students (mean age 13.23 years) regarding their engagement in risk-taking behaviours that may lead to injury. The qualitative study involved 30 students aged 14 to 17 years reporting their experiences of injury and risk-taking. Results: Injury risk behaviours co-occurred among three-quarters of those who reported engaging in any alcohol use or transport or violence related injury risk behaviour. Students described in detail some of these experiences. Conclusions: The selection process of identifying target behaviours for change for an injury prevention program is described. Adolescents’ description of such risk behaviours can inform the process of operationalising and contextualising program content and deciding on evaluation methodology. The design of an effective injury prevention program involves considerable preparatory work and this paper was able to describe the process of identifying the behavioural targets for change that can be operationalised and evaluated in the injury prevention program, SPIY.

Disruption of androgen regulation in the prostate by the environmental contaminant hexachlorobenzene

Hexachlorobenzene (HCB) is a persistent environmental contaminant that has the potential to interfere with steroid hormone regulation. The prostate requires precise control by androgens to regulate its growth and function. To determine if HCB impacts androgen action in the prostate, we used a number of methods. Our in vitro cell-culture-based assay used a firefly luciferase reporter gene driven by an androgen-responsive promoter. In the presence of dihydrotestosterone, low concentrations (0.5-5 nM) of HCB increased the androgen-responsive production of firefly luciferase and high concentrations of HCB (> 10 microM) suppressed this transcriptional activity. Results from a binding assay showed no evidence of affinity between HCB and the androgen receptor. We also tested HCB for in vivo effects using transgenic mice in which the transgene was a prostate-specific, androgen-responsive promoter upstream of a chloramphenicol acetyl transferase (CAT) reporter gene. In 4-week-old mice, the proportion of dilated prostate acini, a marker of sexual maturity, increased in the low HCB dose group and decreased in the high HCB dose mice. In the 8-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to 20 mg/kg/day HCB. Therefore, in vitro and in vivo data suggest that HCB weakly agonizes androgen action, and consequently, low levels of HCB enhanced androgen action but high levels of HCB interfered. Environmental contaminants have been implicated in the rising incidence of prostate cancer, and insight into the mechanisms of endocrine disruption will help to clarify their role.

Correlates of sitting time in working age Australian women : who should be targeted with interventions to decrease sitting time?

Background: While there is emerging evidence that sedentary behavior is negatively associated with health risk, research on the correlates of sitting time in adults is scarce. Methods: Self-report data from 7,724 women born between 1973-1978 and 8,198 women born between 1946-1951 were collected as part of the Australian Longitudinal Study on Women’s Health. Linear regression models were computed to examine whether demographic, family and caring duties, time use, health and health behavior variables were associated with weekday sitting time. Results: Mean sitting time (SD) was 6.60 (3.32) hours/day for the 1973-1978 cohort and 5.70 (3.04) hours/day for the 1946-1951 cohort. Indicators of socio-economic advantage, such as full11 time work and skilled occupations in both cohorts and university education in the mid-age cohort, were associated with high sitting time. A cluster of ‘healthy behaviours’ was associated with lower sitting time in the mid-aged women (moderate/high physical activity levels, non-smoking, non-drinking). For both cohorts, sitting time was highest in women in full-time work, in skilled occupations and in those who spent the most time in passive leisure. Conclusions: The results suggest that, in young and mid-aged women, interventions for reducing sitting time should focus on both occupational and leisure-time sitting.

Participatory design for technological disruption within the agricultural sector

Agricultural adoption of innovation has traditionally been described as slow to diffuse. This paper therefore describes a case study grounded in PD to address a disruptive technology/system within the livestock industry. Results of the process were positive, as active engagement of stakeholders returned rich data. The contribution of the work is also presented as grounds for further design research in the livestock industry.

Designing disruption : linking participatory design and design thinking in technology orientated industries

A vast proportion of companies nowadays are looking to design and are focusing on the end users as a means of driving new projects. However still many companies are drawn to technological improvements which drive innovation within their industry context. The Australian livestock industry is no different. To date the adoption of new products and services within the livestock industry has been documented as being quite slow. This paper investigates how disruptive innovation should be a priority for these technologically focused companies and demonstrates how the use of design led innovation can bring about a higher quality engagement between end user and company alike. A case study linking participatory design and design thinking is presented. Within this, a conceptual model of presenting future scenarios to internal and external stakeholders is applied to the livestock industry; assisting companies to apply strategy, culture and advancement in meaningful product offerings to consumers.